Abstract Despite the prevalence of various infectious and pandemic diseases worldwide, cancer remains the leading cause of death. Clinical approaches for treating cancer vary depending on the tumor type and aggressiveness, including surgery, chemo-, radio-, immune- and hormone therapies. However, the efficacy of these treatments is hindered by the high mortality rate during chemotherapy and radiotherapy, primarily due to severe side effects.This experimental study was conducted on 40 female Sprague-Dawley (SD) rats (n=8). A metronomic treatment strategy was employed using intraperitoneal administration of a small dose of capecitabine loaded onto silica nanoparticles (Cap@SNPs) (377mg/kg) once weekly for a month, either singly or in combination with a low dose of gamma ionizing radiation (IR) (0.5 Gy/5 days) over six sessions, against a 7,12-dimethylbenzaanthracene (DMBA) induced mammary carcinoma model in SD rats. The antitumor effect of Cap@SNPs and/or γ-radiation was assessed by tumor volume measurements, survival analysis, biochemical and haematological parameters and gene expression profiling of selected apoptotic and anti-apoptotic genes. Cell cycle phase distribution, apoptotic cells (Annexin V) and the expression of some immunomodulatory proteins were analyzed by flow cytometry. Histopathological examination was performed using hematoxylin and eosin (H&E) staining. The expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2/neu) proteins in mammary tissue was assessed by immunohistochemistry (IHC). The initial tumor volume across all groups was 32.8 ± 1.8 mm 3 , reaching 86 ± 1.9 mm 3 in the positive control at Day 30 but only 5.3 ± 0.5 mm 3 in the Cap@SNPs + IR group. The death rate decreased from 75% in the positive control to 12.5% in the combined-treated group. Gene expression analysis revealed the downregulation and upregulation of the anti-apoptotic gene ( Bcl2 ) and the apoptotic genes ( Bax , Fas and Caspase-8 ), respectively, in the combination therapy. Flow cytometric analysis showed cell cycle arrest at the G1 phase and increased early apoptosis in the combined-treated group. The findings were verified by histopathological examination and immunohistochemical analysis of mammary tumor tissues. In conclusion, administration of a small capecitabine dose via silica nanoparticle delivery, along with fractionated radiotherapy, achieved substantial tumor regression, improved survival and effective cell-cycle arrest in mammary tumor-bearing rats. These findings support the integration of metronomic chemotherapy with nanoscale drug delivery systems and fractionated radiotherapy as a promising multimodal strategy to enhance anti-tumor efficacy, reduce dose-related toxicity and ultimately improve therapeutic outcomes. Graphical abstract
Ghanim et al. (Fri,) studied this question.